Created to facilitate discussion of rationing and triage in a Bioethics course In response to the following articles: Gatesman and Smith, The Shortage of Essential Chemotherapy Drugs in the United States, NEJM 2010. Chabner, Drug Shortages – A Critical Challenge for the Generic-Drug Market, NEJM 2010.

1. Generic Drug Shortages
Toyin Ola

2. Overview
Articles
National Crisis
Assigning Blame
FDA’s Approach
Specific Example: Methotrexate
2

3. Possible Causes
• Both authors agree the
main cause is economic
• Desire for increased profit
– Oncologists
– Manufacturers
• Gray market
• Reduced reimbursement
from Medicare and
Medicaid
– Average sale price + 6%
markup
• “Leakage” of generic drugs
to overseas markets
Possible Consequences
• Ineffective patient care
• Medication dosage errors
• Price gouging
– Gray market
• Increased cost of cancer
care
• Reduced quality and
contamination
3

4. Proposed Solutions
• Create a national stockpile
(ruled out as impractical)
• Pay practices disease
management fees not based on
chemotherapy sales
• Pay physician salaries
• Set higher prices for generic
drugs
• Decrease prices for brand-
name drugs
• Produce generics in Europe
and Asia
• Allow exclusive licensing of
generic drugs
• Create incentives for
pharmaceutical companies to
produce off-patent drugs
• Changes in definition of generic
drugs in Hatch-Waxman Act of
1984 (bioequivalence)
• Reward past performance when
considering new applications
Gatesman & Smith believe
notification of discontinuance is
an “elusive” solution
4

5. Drug Shortage as a National
Crisis?

6. 2011 Executive Order
• Prescription
drug shortage
tripled between
2005-2010
• Use of sterile
injectable
cancer drugs
increased 20%
(2005-2010)
• Hoarding and
price gouging
are concerns
• Public health
crisis?
6

7. New & Prevented Shortages
7

8. Who, or what, is to blame for
the shortage?

9. According to the FDA
• Quality control
• Notification of discontinuance
9

10. FDA: Disruption in Production
10

11. According to DHHS
• Reasons for shortages (injectable oncology products)
– Costly, specialized equipment required for production
– High quality standards in accordance with Current Good Manufacturing
Processes (CGMPs)
– Drugs’ shelf life
– Usually purchased from wholesale distributors through group purchasing
organizations working on behalf of hospitals and healthcare
– Gray market as a result of drug shortage, not a cause
• Ways to mitigate the shortage
– Decrease demand
• Standardization of care (i.e. clinical guidelines)
– Increase supply elasticity
– Tailoring FDA’s regulatory response
11

12. FDA’s Approach to Drug
Shortage

13. FDA’s Proposed Rule
Food and Drug Administration Safety and Innovation Act (FDASIA)
• July 2012
“Applicants would be required to notify FDA of a permanent discontinuance or
an interruption in supply if the drug or biological product is a prescription
product that is life supporting, life sustaining, or intended for use in the
prevention or treatment of a debilitating disease or condition, including any
such drug used in emergency medical care or during surgery, and excluding
radiopharmaceutical products”
• FDA defines life supporting/sustaining  “...essential to, or that
yields information that is essential to, the restoration or continuation
of a bodily function important to the continuation of human life”
• Notification must be done electronically
• 6 months’ advance notice (or within 5 business days of the
permanent discontinuance/interruption in manufacturing)
13

14. FDA Strategic Plan for Preventing &
Mitigating Drug Shortages
14

15. FDA Strategic Plan for Preventing &
Mitigating Drug Shortages
• Mitigation Strategies:
– Identify the extent of the shortfall and determine if other manufacturers are
willing and able to increase production
– Expedite FDA inspections and reviews of submissions from manufacturers
attempting to restore production and from competing manufacturers who are
interested in starting new production or increasing existing production of
products in shortage
– Exercise temporary enforcement discretion for new sources of medically
necessary drugs
– Work with the manufacturer to ensure adequate investigation into the root
cause of the shortage
– Develop risk mitigation measures for a batch(es) of product initially not
meeting established standards
All focused on preventing production disruptions from turning into
actual shortages
15

16. FDA Strategic Plan for Preventing &
Mitigating Drug Shortages
Tasks for Goal #1
• Streamline internal FDA
processes
• Improve data and response
tracking
• Clarify roles/responsibility of
manufacturers
– Ex: more clinical trials
• Enhance public
communications about
shortages
Tasks for Goal #2
• Develop methods to
incentivize and prioritize
manufacturing quality
• Use regulatory science to
identify early warning
signals of shortages
• Increase knowledge to
develop new strategies to
address shortages
– Ex: development of best
practices to avoid
disruptions
16

17. American Society of Healthsystem
Pharmacists (ASHP)
Guidelines on Managing Drug Product Shortages
“In the event of prolonged shortages of drug products, especially
when alternative therapies are limited, a patient priority plan may
be needed. A multi-disciplinary team should develop criteria for
the use of the product.”
“Carefully written guidelines should be provided to assist frontline
pharmacists to appropriately assess and respond to medication
orders for drug products under a patient priority limitation.”
17

18. The Specific Case of
Methotrexate (MTX)

19. Usage
• According to WHO, methotrexate was being used to treat the
following disorders in the pediatric population as of 2008:
juvenile idiopathic arthritis (JIA)
uveitis associated with JIA
ulcerative colitis
psoriasis
psoriatic arthritis
vasculitides
Wegener’s granulomatosis,
Henoch Schonlein purpura
vasculitis
sarcoidosis
systemic lupus
erythematosous
eosinophilic fasciitis
Crohn’s disease
acute lymphoblastic
leukemia (ALL)
non-Hodgkin’s
lymphoma
meningeal leukemia
osteosarcoma
19

20. Shortage
• According to ASHP, there is still a shortage of injectable MTX as
of January 24, 2014
– Not included on FDA’s shortage list
– Ben Venue, supplier to Bedford Laboratories, has stopped
production
• Bedford, OH plant scheduled to close
– Other manufacturers are back-ordered
• Release dates in later January and February 2014
– Record of failed quality control inspections
20

21. Shortage
21

22. Distribution
ALL
• MTX is part of all three stage
of treatment—induction,
intensification, and
maintenance
– VAMP regimen: vincristine,
amethopterin
(methotrexate), 6-MP, and
prednisone
– Additional infused MTX
helps prevent involvement of
the central nervous system
– Oral MTX is typically
administered for 2-3 years
after remission is achieved
JIA
• MTX dosage is generally 15-
30mg once-a-week
• Usually. MTX is administered
orally, but injections are given
to patients who do not
tolerate the oral medication
well
• Treatment with MTX lasts
indefinitely, even after a
patient has achieve remission
• Use generally continues even
when new medications are
added
22

23. Discussion Points: Emphasis
• Should the focus be on...
– Preventing increased use of MTX?
 Public health initiative
– Preventing shortage?
• Manufacturing and notification
– Just distribution during shortage?
• Clinical guidelines
• Public policy
• Other consideration: just procedure vs. fair outcome
23

24. Discussion Points: Rationing
• Triage?
– Priority goes to the sickest
– Priority goes to least sick
– Refuse treatment if low likelihood of survival
• Clinical judgment based on a threshold?
– Ex: Patient must have ___ white blood cell count (or other
quantifiable measure of how active the disease is)
• Separate protocol for each form of MTX?
– Ex: ALL patients have priority for injectable, non-preservative
MTX
24

25. Distribution: Rationing
• Revisit some rationing concepts presented in
Beauchamp & Childress:
– Using age
• Chance at ‘normal’ life span
– Using a lottery
– Using social worth
• Use parents’ success as indicator of child’s potential?
– Using fair-opportunity rule
• Consider vulnerabilities other than illness (social lottery)?
25

26. Outside Sources Consulted
(not on syllabus)
• http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm257745.htm
• http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm373044.htm
• http://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM372566.pdf
• http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm050792.htm
• http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm050796.htm
• http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentst
otheFDCAct/FDASIA/ucm313121.htm
• http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentst
otheFDCAct/FDASIA/ucm365919.htm
• http://www.whitehouse.gov/the-press-office/2011/10/31/executive-order-reducing-prescription-drug-shortages
• http://aspe.hhs.gov/sp/reports/2011/DrugShortages/ib.shtml
• http://www.ashp.org/drugshortages/current/bulletin.aspx?id=26
• http://www.ashp.org/s_ashp/docs/files/BP07/Procure_Gdl_Shortages.pdf
• http://bloodjournal.hematologylibrary.org/content/111/5/2573.full.pdf
• http://www.mdanderson.org/publications/making-cancer-history/excerpts-from-making-cancer-history/making-cancer-
history-revolutionizing-the-treatment-of-childhood-leukemia.html
• http://www.nytimes.com/health/guides/disease/acute-lymphocytic-leukemia-all/treatment-during-remission.html
• http://emedicine.medscape.com/article/2004705-overview
• https://www.federalregister.gov/articles/2013/11/04/2013-25956/permanent-discontinuance-or-interruption-in-
manufacturing-of-certain-drug-or-biological-products#h-12
• Boehm, Garth et. al. (2013). Development of the generic drug industry in the US after the Hatch-Waxman Act of 1984.
Acta Pharmaceutica Sinica B 2 (5): 297-311. Retrieved from:
http://www.sciencedirect.com/science/article/pii/S2211383513000762.
26